The present invention relates to a process for preparing N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline (hereinafter referred to as "enalapril") having the formula (I): ##STR1## wherein an asterisk represents (S)-configuration with respect to the asymmetric carbon atom, which is a main component of N-[1(S)-ethoxy-carbonyl-3-phenylpropyl]-L-aranyl-L-proline maleate (USAN: Enalapril Maleate) which is expected to be used as an antihypertensive agent due to an excellent Angiotensin Converting Enzyme (ACE) inhibitory activity.
As a method for preparing the enalapril, there has already been known a method by a reductive amination reaction, in which a Schiff's base (IV) obtained by condensing L-alanyl-L-proline (III) with ethyl .alpha.-oxo-.gamma.-phenylbutyrate (II) is reduced with hydrogen gas in the presence of catalyst such as palladium/carbon or sodium cyanoborohydride (NaBH.sub.3 CN) [Japanese Unexamined Patent Publication No. 81845/1980 and J. Org. Chem. 49 (15), 2816 (1984)]. ##STR2##
ACE inhibitory activity of the enalapril is closely related to a configuration at an asymmetric carbon atom. For the desired activity, it is necessary that the enalapril is an optically active compound with (S)-configuration with respect to all the three asymmetric carbon atoms, i.e. (SSS)-configuration. According to the above method for synthesizing the enalapril by the reductive amination reaction, however, a mixture of (SSS)-configuration and (RSS)-configuration is prepared since both (S)-configuration and (R)-configuration of N-[1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline are produced with respect to the asymmetric carbon atom in the phenylbutyric acid part of the compound produced by the reduction of the Schiff's base having the formula (VI). For this reason, various studies have been made in order to advantageously obtain the enalapril with the desired (SSS)-configuration. When the catalytic reduction is carried out with a catalyst of palladium/carbon, well utilizing the steric structure of the L-alanyl-L-proline portion, the asymmetric induction occurs to some extent. However, a ratio of (SSS)-configuration/(RSS)-configuration is still 62/38 and thus a complicated optical resolution procedure is required in order to obtain the desired compound with (SSS)-configuration, and moreover, a yield of the desired compound with (SSS)-configuration is quite low, i.e. less than 50% due to the production of a large amount of the compound with (RSS)-configuration, although each reaction proceeds in high efficiency. Therefore, starting materials which are expensive and prepared by many steps, ethyl .alpha.-oxo-.gamma.-phenylbutyrate (II) and L-alanyl-L-proline (III), may be wasted by this method. Also, in the reductive amination reaction, when the reaction to form the Schiff's base and the reduction of the Schiff's base are carried out separately, even (SRS)-configuration and (RRS)-configuration derived from racemization of the alanine portion are also inadvantageously by-produced in addition to (SSS)-configuration and (RSS)-configuration, since the Schiff's base prepared in the reaction substantially has a tendency to cause racemization. In order to avoid racemization of the Schiff's base, it has been attempted to prepare the Schiff's base in situ in the reduction system. However, ethyl .alpha.-oxo-.gamma.-phenylbutyrate (II), which is easily reduced by nature, is not only used for producing the Schiff's base but also reduced to form a by-product such as ethyl .alpha.-hydroxy-.gamma.-phenylbutyrate, which results in a competitive wasteful consumption of the compound (II), and thus 2 to 3 times molar amount of ethyl .alpha.-oxo-.gamma.-phenylbutyrate must be used, which leads to a disadvantage in an operation such that the complicated extraction procedure is required for isolating the desired compound from the reaction mixture including a large amount of ethyl .alpha.-hydroxy-.gamma.-phenylbutyrate by-produced.
As aforementioned, the method by the reductive amination reaction cannot be advantageous for the industrial production of the enalapril in viewpoint of economy and operability.
As the result of the present inventors' continuous study to establish an economical, simple and efficient process of the industrial production of the enalapril, it was found that N-carboxyanhydride of N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine can be reacted with L-proline quite easily in the presence of a base to produce the enalapril with almost quantitative yield.